The adenosine aspartate effect to restore the proliferative capacity of hepatic tissue, stopping the fibrogenesis that occurs in hepatic alterations ending in hepatic cirrhosis, without caring about the aetiological agent, is well known. The adenosine administration in its aspartate salt form, has given beneficial results in controlling cirrhosis of the liver, Mexican patent 207422, reducing the accumulation of collagen remarkably enhancing the histological symptoms of the cryogenic process, which is accompanied by an improvement in the hepatic function tests and the liver energetic parameters. The increase of cell energy availability and collagenolytic activity of the fibrotic liver induced by the adenosine administration, is related to the normalization of the intracellular redox state due to the protection of the mitochondrial function; likewise, it increases the cytochrome p450 making the detoxification processes easier (Chagoya de Sanchez V., Hernández-Muñoz R., Yañez L., Vidrio S., Díaz-Muñoz M. Possible mechanism of adenosine protection in carbon tetrachloride acute hepatoxicity. Role of adenosine by-products and glutathione peroxidase. J., Biochem. Toxicollogy (1995) 10: 41-50). All these changes promote a fast hepatic proliferative response, which is severely depressed in the cirrhotic liver.
It is well known that adenosine aspartate increases the energy metabolism at the expense of the mitochondrial metabolism restoring the normal energy condition reduced by toxic agents that damage the hepatocytes thereby protecting the mitochondrial function and structure. Likewise, its antioxidant effect avoids free radicals propagation and damage caused to proteins and DNA by the hepatotoxic agents. On the other hand, it restores to normal the regenerative response of the cirrhotic liver measured by the activity of thymidine kinase and by the mitotic index. (Hernández-Muñoz R, Díaz-Muñoz M, Suárez-Cuenca J A, Trejo-Solis C, López V, Sánchez-Sevilla L, Yañez L, and Chagoya de Sánchez V. Adenosine reverses a preestablished CCl4—induced micronodular cirrosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats. Hepatology (2001) 34: 677-687.) Likewise, it has been seen that it reduces serum levels of alpha-fetoprotein in cirrhotic patients who present slightly high levels of this hepatic cancer marker; on the other hand, it helps the liver to donate purine backbones to the extrahepatic tissues (Chagoya de Sánchez V, Hernández-Muñoz R, Díaz-Muñoz M, Villalobos R, Glender W, Vidrio S, Suárez J, Yañez L Circadian variations of adenosine level in blood and liver and its possible physiological significance Life Sciences (1983) 33: 1057-1064), this effect generates myeloprotection. Finally, it reorganizes the extracellular matrix by modifying the effect of the adhesion proteins as integrins and adhesins and it induces transformed cell apoptosis, these effects could avoid cancer development and hepatic metastasis. Meanwhile, the effect of a synthetic agonist of the A3 adenosine receptor which inhibits the carcinogenic growth of colon, melanoma, prostate, as well as liver and lung metastasis showing anticarcinogenic and chemoprotective effect has been shown. (Fishman P, Bar-Yehuda S, Barer F, Madi L, Multan A S, Pathak S, The A3 adenosine receptor as a new target for cancer therapy and chemoprotection. Exp Cell Res (2001) 269:230-236.)
From the aforementioned, it is derived that adenosine salts, particularly adenosine aspartate, might be used in a pharmaceutical formulation to prepare drugs for the support therapy of the usual treatment against colon, melanoma, prostate cancer, as well as liver cancer and lung metastasis. In the present invention, given the experience of the research team, it was decided to demonstrate the adenosine aspartate effect mainly in liver cancer, without limiting other kinds of tumors that respond to the activation of the A3 adenosine receptor.
The hepatocellular carcinoma is responsible of 80% to 90% of all the types of liver cancer. Its incidence is greater in men than in women and it attacks mainly people between 50 and 60 years old. This disease is more common in some parts of Africa and Asia than in North America, South America, and Europe. Usually, the cause of liver cancer is cirrhosis or scarring of said organ. Cirrhosis could be caused by viral hepatitis, especially hepatitis B and C, excessive alcohol consumption, certain liver autoimmune diseases, hemochromatosis, and a great number of pathologies.
In order to detect liver cancer, some markers are used, such as γ-glutamyltranspeptidase level measurement called GGT. This test is used to detect liver, bile ducts and kidneys diseases; and also to differentiate liver or bile ducts disorders from bone disease.
GGT takes part in the amino acid transference through the cell membrane and in the glutathione metabolism as well, and this enzyme is in high concentrations in the liver, bile ducts and kidney.
GGT is measured in combination with other tests. Particularly, the alkaline phosphatase is higher in hepatobiliary and bone diseases and GGT is higher in hepatobiliar diseases, but not in bone disease; hence, a patient with a high alkaline phosphatase level and a normal GGT level probably suffers a bone disease but not a hepatobiliar one. Normal values of this marker are in a range of 0 to 5 UI/L, and the higher to normal levels could show congestive heart failure, cholestasis, cirrhosis, ischemia, and hepatic necrosis, hepatic tumor, and hepatitis.
Now then, from knowing the action mechanism and the utility that adenosine aspartate has demonstrated to prevent hepatic cirrhosis, and bearing in mind the existing relationship between this condition and liver cancer development, this invention was developed using adenosine aspartate to formulate a drug to prevent cancer development, mainly hepatic cancer due to its high relationship with cirrhosis. Likewise, when pre-cancerous lesions have been established, adenosine aspartate is used to reverse the process.